Depression and Post-Traumatic Stress Disorder (PTSD) are more prevalent in young women than men. Genetic studies link the CREB1 gene with recurrent depression in women but not men, supporting a neurobiological basis for this gender discrepancy. Both depression and PTSD involve dysfunction of the prefrontal cortex (PFC), a brain region that is 1) critical for regulating behavior, thought and affect, and 2) dysfunctional during exposure to uncontrollable stress. Stress is a major risk factor for depression, and life-threatening stress can cause PTSD. We hypothesize that estrogen promotes sensitivity to stress, rendering women more susceptible to PFC dysfunction, and thus to stress-related disorders. The proposed research will begin to identify the neurobiological mechanisms through which estrogen exacerbates stress-induced PFC dysfunction. Research in male rats has shown that stress-induced PFC dysfunction arises from excessive catecholamine release in PFC, activating protein kinases A and C, which in turn phosphorylate CREB. Interestingly, alpha-1 adrenoceptors (al R) drive this stress response, while alpha-2A adrenoceptors (a2AR) protect the PFC from stress, and estrogen is known to increase the expression of a1R and reduce the expression of a2AR. Our initial results show that cycling female rats with high levels of circulating estrogen are impaired by mild injection stress, by low doses of a pharmacological stressor, FG7142, and by brief periods of restraint stress which have no effect in males or females with low levels of estrogen. The proposed research will extend these studies to ovariectomized rats with and without estrogen replacement. Aim 1 will test the hypothesis that estrogen amplifies the cognitive and biochemical responses to restraint stress. Biochemical characterization will include measures of a1AR and a2AR expression, catecholamine turnover and phospho-CREB in PFC. Aim 2 will begin to explore the contribution of these biochemical changes to PFC cognitive function, testing whether the increased expression of a1R in the PFC of estrogen-treated rats renders them more sensitive to cognitive impairment. This research will begin to reveal how estrogen amplifies the neurochemical cascades that lead to activation of CREB and dysfunction of the PFC during stress